title: Biliverdin reductase plays a crucial role in hypoxia-induced chemoresistance in human glioblastoma.
abstract: Hypoxia-induced alterations in the cellular redox status play a critical role in the development of hypoxia-induced chemoresistance in cancer cells. Human biliverdin reductase (hBVR), an enzyme involved in the conversion of biliverdin into bilirubin in heme metabolism, was recently identified as an important cytoprotectant against oxidative stress and hypoxia. However, the role of hBVR on hypoxia-induced drug resistance has not been previously investigated. Using human glioblastoma cell lines, we evaluated the potential role of hBVR in hypoxia-induced drug resistance. We found that hypoxia caused a significant increase in hBVR expression in glioblastoma cells that was accompanied by chemoresistance. We also observed that siRNA-based targeting of hBVR genes attenuated the hypoxia-induced chemoresistance. Furthermore, knocking down hBVR induced a marked increase in the levels of intracellular reactive oxygen species under hypoxic conditions, and the chemosensitizing effect of hBVR depletion was reversed by pretreatment with the antioxidant N-acetylcysteine. These findings suggest that hBVR significantly contributes to the modulation of hypoxia-induced chemoresistance of glioblastoma cells by adjusting their cellular redox status.
authors.affiliation: College of Oriental Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Sung Su
authors.initials: SS
authors.lastname: Kim
authors.forename: Sin
authors.initials: S
authors.lastname: Seong
authors.forename: Seong Hyeon
authors.initials: SH
authors.lastname: Lim
authors.forename: Sung Young
authors.initials: SY
authors.lastname: Kim
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000201:enzymology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000201:enzymology*; D006801:Humans; D010084:Oxidation-Reduction; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D017239:Paclitaxel / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D017382:Reactive Oxygen Species; D003606:Dacarbazine; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D017239:Paclitaxel; D000077204:Temozolomide
keywords: Biliverdin reductase; Chemoresistance; GBM; Glioblastoma; Glioblastoma multiforme; HO; Heme oxygenase; Hypoxia; N-acetylcysteine; NAC; PTX; Paclitaxel; ROS; Reactive oxygen species; TMZ; Temozolomide; biliverdin reductase; hBVR; paclitaxel; reactive oxygen species; temozolomide